tbuckley/cabot-search huggingface dataset:
Gliflozins in the Management of Cardiovascular Disease
Authors: Eugene Braunwald
Journal: New England Journal of Medicine (2022)

Gliflozins — sodium–glucose cotransporter 2 inhibitors — lower blood glucose and glycated hemoglobin in patients with type 2 diabetes without causing hypoglycemia. The agents also improve cardiac function in patients who have heart failure with or without type 2 diabetes and improve renal function, with few adverse effects.
Should we rewrite the natural history and prognosis of pulmonary Langerhans cell histiocytosis?
Authors: Sergio Harari, Davide Elia
Journal: European Respiratory Journal (2022)

<b>The natural history and clinical prognosis of PLCH have changed, since its first description. A long-term follow-up is recommended in order to prevent the development of malignancies.</b>https://bit.ly/3KmGbNo
The hallmarks of aging in Ataxia-Telangiectasia
Authors: Julio Aguado, Cecilia Gómez-Inclán, Hannah C. Leeson, Martin F. Lavin, Yosef Shiloh, Ernst J. Wolvetang
Journal: Ageing Research Reviews (2022)

Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches of cellular metabolism, redox and mitochondrial homeostasis, and cell cycle regulation. A-T is a complex disorder characterized mainly by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. It is increasingly recognized that the premature aging component of A-T is an important driver of this disease, and A-T is therefore an attractive model to study the aging process. This review outlines the current state of knowledge pertaining to the molecular and cellular signatures of aging in A-T and proposes how these new insights can guide novel therapeutic approaches for A-T.
Neat1 promotes acute kidney injury to chronic kidney disease by facilitating tubular epithelial cells apoptosis via sequestering miR-129-5p
Authors: Tongtong Ma, Hongwei Li, Hui Liu, Yili Peng, Tong Lin, Zhiya Deng, Nan Jia, Zhongqing Chen, Peng Wang
Journal: Molecular Therapy (2022)

Acute kidney injury (AKI) is increasingly identified as a crucial risk factor for progression to CKD. However, the factors governing AKI to CKD progression remain largely unknown. By high-throughput RNA sequencing, we found that Neat1_2, a transcript variant of Neat1, was upregulated in 40-min ischemia/reperfusion injury (IRI), which resulted in the development of renal fibrotic lesions. The upregulation of Neat1_2 in hypoxia-treated TECs was attributed to p53 transcriptional regulation. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrated that Neat1_2 promoted apoptosis of injured TECs induced by IRI and caused tubulointerstitial inflammation and fibrosis. Mechanistically, Neat1_2 shares miRNA response elements with FADD, CASP-8, and CASP-3. Neat1_2 competitively binds to miR-129-5p and prevents miR-129-5p from decreasing the levels of FADD, CASP-8, and CASP-3, and ultimately facilitates TEC apoptosis. Increased expression of Neat1_2 associated with kidney injury and TEC apoptosis was recapitulated in human AKI, highlighting its clinical relevance. These findings suggest that preventing TEC apoptosis by hindering Neat1_2 expression may be a potential therapeutic strategy for AKI to CKD progression. Acute kidney injury (AKI) is increasingly identified as a crucial risk factor for progression to CKD. However, the factors governing AKI to CKD progression remain largely unknown. By high-throughput RNA sequencing, we found that Neat1_2, a transcript variant of Neat1, was upregulated in 40-min ischemia/reperfusion injury (IRI), which resulted in the development of renal fibrotic lesions. The upregulation of Neat1_2 in hypoxia-treated TECs was attributed to p53 transcriptional regulation. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrated that Neat1_2 promoted apoptosis of injured TECs induced by IRI and caused tubulointerstitial inflammation and fibrosis. Mechanistically, Neat1_2 shares miRNA response elements with FADD, CASP-8, and CASP-3. Neat1_2 competitively binds to miR-129-5p and prevents miR-129-5p from decreasing the levels of FADD, CASP-8, and CASP-3, and ultimately facilitates TEC apoptosis. Increased expression of Neat1_2 associated with kidney injury and TEC apoptosis was recapitulated in human AKI, highlighting its clinical relevance. These findings suggest that preventing TEC apoptosis by hindering Neat1_2 expression may be a potential therapeutic strategy for AKI to CKD progression.
Endoscopic full-thickness resection for polyps involving the appendiceal orifice: not yet ready for prime time
Authors: Saif Ullah, Bing-Rong Liu
Journal: Endoscopy (2022)

See also: Endoscopic full-thickness resection of polyps involving the appendiceal orifice: a multicenter international experienceEndoscopy 2022; 54(01): 16-24DOI: 10.1055/a-1345-0044
Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: A population-based cohort study
Authors: Adeel M. Khan, Thita Chiasakul, Robert Redd, Rushad Patell, Ellen P. McCarthy, Donna Neuberg, Jeffrey I. Zwicker
Journal: PLoS Medicine (2022)

Background Direct oral anticoagulants (DOACs) have comparable efficacy with low-molecular-weight heparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE). Whether there is a mortality benefit of DOACs compared with warfarin in the management of VTE in cancer is not established. Methods and findings Utilizing the United States’ Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases from 2012 through 2016, we analyzed overall survival in individuals diagnosed with a primary gastric, colorectal, pancreas, lung, ovarian, or brain cancer and VTE who received a prescription of DOAC or warfarin within 30 days of VTE diagnosis. Patients were matched 1:2 (DOAC to warfarin) through exact matching for cancer stage and propensity score matching for age, cancer site, cancer stage, and time interval from cancer to VTE diagnosis. The analysis identified 4,274 patients who received a DOAC or warfarin for the treatment of VTE within 30 days of cancer diagnosis (1,348 in DOAC group and 2,926 in warfarin group). Patients were of median age 75 years and 56% female. Within the DOAC group, 1,188 (88%) received rivaroxaban, and 160 (12%) received apixaban. With a median follow-up of 41 months, warfarin was associated with a statistically significantly higher overall survival compared to DOACs (median overall survival 12.0 months [95% confidence interval (CI): 10.9 to 13.5] versus 9.9 months [95% CI: 8.4 to 11.2]; hazard ratio (HR) 0.85; 95% CI: 0.78 to 0.91; p &lt; 0.001). Observed differences in survival were consistent across subgroups of cancer sites, cancer stages, and type of VTE. The study limitations include retrospective design with potential for unaccounted confounders along with issues of generalizability beyond the cancer diagnoses studied. Conclusions In this analysis of a population-based registry, warfarin was associated with prolonged overall survival compared to DOACs for treatment of cancer-associated VTE.
An LSC-based MRD assay to complement the traditional MFC method for prediction of AML relapse: a prospective study
Authors: Si-Qi Li, Lan-Ping Xu, Yu Wang, Xiao-Hui Zhang, Huan Chen, Yu-Hong Chen, Feng-Rong Wang, Wei Han, Yu-Qian Sun, Chen-Hua Yan, Meng Lv, Fei-Fei Tang, Xiao-Dong Mo, Yan-Rong Liu, Kai-Yan Liu, Ying-Jun Chang, Xiao-Jun Huang
Journal: Blood (2022)
Infant Visual Brain Development and Inherited Genetic Liability in Autism
Authors: Jessica B. Girault, Kevin Donovan, Zoë Hawks, Muhamed Talovic, Elizabeth Forsen, Jed T. Elison, Mark D. Shen, Meghan R. Swanson, Jason J. Wolff, Sun Hyung Kim, Tomoyuki Nishino, Savannah Davis, Abraham Z. Snyder, Kelly N. Botteron, Annette M. Estes, Stephen R. Dager, Heather C. Hazlett, Guido Gerig, Robert McKinstry, Juhi Pandey, Robert T. Schultz, Tanya St. John, Lonnie Zwaigenbaum, Alexandre Todorov, Young Truong, Martin Styner, John R. Pruett, John N. Constantino, Joseph Piven
Journal: American Journal of Psychiatry (2022)

Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings.
Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap
Authors: Xiaofan Tu, Richard Y. Kim, Alexandra C. Brown, Emma de Jong, Bernadette Jones-Freeman, Md Khadem Ali, Henry M. Gomez, Kurtis F. Budden, Malcolm R. Starkey, Guy J.M. Cameron, Svenja Loering, Duc H. Nguyen, Prema Mono Nair, Tatt Jhong Haw, Charlotte A. Alemao, Alen Faiz, Hock L. Tay, Peter A.B. Wark, Darryl A. Knight, Paul S. Foster, Anthony Bosco, Jay C. Horvat, Philip M. Hansbro, Chantal Donovan
Journal: Journal of Allergy and Clinical Immunology (2022)
Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies
Authors: Mathieu Larroquette, Jean-Philippe Guegan, Benjamin Besse, Sophie Cousin, Maxime Brunet, Sylvestre Le Moulec, François Le Loarer, Christophe Rey, Jean-Charles Soria, Fabrice Barlesi, Alban Bessede, Jean-Yves Scoazec, Isabelle Soubeyran, Antoine Italiano
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles. Methods Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration. Results Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of ITGAM , CD27, and CCL5 in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of CSF1R in the tumors of responders. Analysis of three independent data sets confirmed that high CSF1R expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p&lt;0.001) under ICB treatment. Conclusions Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of CD27 , ITGAM, and CCL5 gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.
Celebrating a decade of the<i>Journal for ImmunoTherapy of Cancer</i>
Authors: Pedro J Romero, James L Gulley, Patrick Hwu, Mary Dean, Samuel Million-Weaver
Journal: Journal for ImmunoTherapy of Cancer (2022)

The year 2022 marks an important milestone for the Journal for ImmunoTherapy of Cancer (JITC ) as the journal's 10th anniversary. Similar to the immunotherapy field as a whole, JITC has experienced tremendous evolution and growth over the past decade. This editorial looks back over the journal's
Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Manish A. Shah, Kohei Shitara, Florian Lordick, Yung-Jue Bang, Niall C. Tebbutt, Jean-Phillippe Metges, Kei Muro, Keun-Wook Lee, Lin Shen, Sergei Tjulandin, John L. Hays, Naureen Starling, Rui-Hua Xu, Keren Sturtz, Marilyn Fontaine, Cindy Oh, Emily M. Brooks, Bo Xu, Wei Li, Chiang J. Li, Laura Borodyansky, Eric Van Cutsem
Journal: Clinical Cancer Research (2022)

To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 intravenously weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade {greater than or equal to}3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade {greater than or equal to}3 diarrhea reported in 16.2% and 1.4%, respectively.Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade {greater than or equal to}3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.
Arrhythmias as Presentation of Genetic Cardiomyopathy
Authors: J. Lukas Laws, Megan C. Lancaster, M. Ben Shoemaker, William G. Stevenson, Rebecca R. Hung, Quinn Wells, D. Marshall Brinkley, Sean Hughes, Katherine Anderson, Dan Roden, Lynne W. Stevenson
Journal: Circulation Research (2022)

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.
Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort
Authors: A. Italiano, A. Bessede, M. Pulido, E. Bompas, S. Piperno-Neumann, C. Chevreau, N. Penel, F. Bertucci, M. Toulmonde, C. Bellera, J. P. Guegan, C. Rey, C. Sautès-Fridman, A. Bougoüin, C. Cantarel, M. Kind, M. Spalato, B. Dadone-Montaudie, F. Le Loarer, J. Y. Blay, W. H. Fridman
Journal: Nature Medicine (2022)
Management of gout following 2016/2017 European (EULAR) and British (BSR) guidelines: An interrupted time-series analysis in the United Kingdom
Authors: Mark D Russell, Andrew I Rutherford, Benjamin Ellis, Sam Norton, Abdel Douiri, Martin C Gulliford, Andrew P Cope, James B Galloway
Journal: The Lancet Regional Health - Europe (2022)

Following studies reporting sub-optimal gout management, European (EULAR) and British (BSR) guidelines were updated to encourage the prescription of urate-lowering therapy (ULT) with a treat-to-target approach. We investigated whether ULT initiation and urate target attainment has improved following publication of these guidelines, and assessed predictors of these outcomes.We used the Clinical Practice Research Datalink to assess attainment of the following outcomes in people (n = 129,972) with index gout diagnoses in the UK from 2004-2020: i) initiation of ULT; ii) serum urate ≤360 µmol/L and ≤300 µmol/L; iii) treat-to-target urate monitoring. Interrupted time-series analyses were used to compare trends in outcomes before and after updated EULAR and BSR management guidelines, published in 2016 and 2017, respectively. Predictors of ULT initiation and urate target attainment were modelled using logistic regression and Cox proportional hazards.37,529 (28.9%) of 129,972 people with newly-diagnosed gout had ULT initiated within 12 months. ULT initiation improved modestly over the study period, from 26.8% for those diagnosed in 2004 to 36.6% in 2019 and 34.7% in 2020. Of people diagnosed in 2020 with a serum urate performed within 12 months, 17.1% attained a urate ≤300 µmol/L, while 36.0% attained a urate ≤360 µmol/L. 18.9% received treat-to-target urate monitoring. No significant improvements in ULT initiation or urate target attainment were observed after updated BSR or EULAR management guidance, relative to before. Comorbidities, including chronic kidney disease (CKD), heart failure and obesity, and diuretic use associated with increased odds of ULT initiation but decreased odds of attaining urate targets within 12 months: CKD (adjusted OR 1.61 for ULT initiation, 95% CI 1.55 to 1.67; adjusted OR 0.51 for urate ≤300 µmol/L, 95% CI 0.48 to 0.55; both p < 0.001); heart failure (adjusted OR 1.56 for ULT initiation, 95% CI 1.48 to 1.64; adjusted OR 0.85 for urate ≤300 µmol/L, 95% CI 0.76 to 0.95; both p < 0.001); obesity (adjusted OR 1.32 for ULT initiation, 95% CI 1.29 to 1.36; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.58 to 0.65; both p < 0.001); and diuretic use (adjusted OR 1.49 for ULT initiation, 95% CI 1.44 to 1.55; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.57 to 0.66; both p < 0.001).Initiation of ULT and attainment of urate targets remain poor for people diagnosed with gout in the UK, despite updated management guidelines. If the evidence-practice gap in gout management is to be bridged, strategies to implement best practice care are needed.National Institute for Health Research.
Pancreatic duct dilatation and pancreatic head mass caused by the rare finding of a whole Ascaris within the pancreatic duct
Authors: Wei Liu, Chun Liu, Fang Lyu, Pengfei Li, Yao Ning, Chao He
Journal: Endoscopy (2022)

A 56-year-old woman was transferred from an outside hospital owing to concern about pancreatic duct (PD) obstruction and a pancreatic head mass. The patient had been admitted 1 week prior to the transfer with abdominal pain radiating to the waist and back, accompanied by nausea and vomiting. Her symptoms had since resolved with supportive measures, including anti-inflammatories and analgesics. Physical examination on admission did not reveal a jaundiced complexion and her abdomen was soft without tenderness. Outpatient laboratory results demonstrated a mildly elevated cancer antigen 199 (CA199) at 41.02 U/mL, but liver function panel, and serum and urinary amylase were within the normal ranges. Abdominal computed tomography (CT) at the previous hospital had shown PD dilatation and pancreatic head enlargement ([Fig. 1]).